The present invention relates generally to the field of small molecule therapeutics, specifically, the vascular damaging agent, or vascular disrupting agent carbamic acid N-[6-[[4-[[(2S)-2-amino-1-oxopropyl]amino]phenyl]thio]-1H-benzimidazol-2-yl]-methyl ester di-hydrochloride or denibulin di-hydrochloride (MN-029.2HCl). The formation of neovasculature by angiogenesis is a key pathological step in the development and progress of many diseases, such as cancer, psoriasis, rheumatoid arthritis, macular degeneration and atherosclerotic plaques.
In the cancer field, for example, tumor growth requires the formation of neovasculature to supply critically important nutrients and oxygen to the growing tumor. The formed vascular tissue also serves as a conduit for removing toxic metabolic by-products as well as drug agents from the vicinity of the tumor.
Compounds that damage or prevent neovasculature may find use, therefore, in the treatment of the above mentioned diseases. Several compounds and their pharmaceutically acceptable salts are known to have vascular damaging activity. These agents include, for example, combretastatin A 1 and combretastatin A4 (D. J. Chaplin et al., British J. Cancer 27, S86-S88, 1996), combretastatin A4 phosphate (Dark et al., Cancer Research 57, 1829-1834, 1997), combretastatin A1 phosphate (Holwell et al. Proc. Amer. Assoc. Cancer Res. 41, 1363, 2000), AC7700 (Hori et al. Jpn. J. Cancer Res. 90, 1026-1038, 1999), colchinol derivatives (Davis et al., WO 98/01977 and Davis et al. WO00/40529), benzimidazole derivatives (Davis, WO00/41669), the flavone acetic acids, for example 5,6-dimethylxanthenone acetic acid (Zwi, Pathology, 26, 161-9, 1994) and colchicine (Baguley et al. Eur J Cancer 27, 482-7, 1991).
MN-029 is a known vascular damaging agent that is currently being tested as a candidate therapeutic for treating cancer. The present invention focuses on the discovery of a di-hydrochloride salt form of MN-029, which is useful as a therapeutic agent and exhibits certain advantages over other salt forms of MN-029, as further described in what follows. Pharmaceutically acceptable compositions of the di-hydrochloride salt form of MN-029 are described herein. The present invention also pertains to a method of treating, or the use of the inventive composition in treating the aforementioned diseases by administrating to a subject in need thereof the inventive composition of MN-029 or a combination of the inventive composition with known chemotherapeutics, or in conjunction with radiation and chemo-radiation protocols.